Bottom Line:
Using a murine model of penicillin V-induced systemic anaphylaxis, we show an autoregulatory cascade of biphasic anaphylactic reactions.The induction of NF-kappaB activity is accompanied by TNF-alpha production, which, in turn, promotes late phase PAF synthesis.This secondary wave of PAF production leads eventually to the late phase of anaphylactic reactions.

Affiliation: Department of Immunology, University National Medical School, Chonju, Chonbuk, 561-182, South Korea.

ABSTRACTAnaphylaxis is a life-threatening systemic allergic reaction with the potential for a recurrent or biphasic pattern. Despite an incidence of biphasic reaction between 5 and 20%, the molecular mechanism for the reaction is unknown. Using a murine model of penicillin V-induced systemic anaphylaxis, we show an autoregulatory cascade of biphasic anaphylactic reactions. Induction of anaphylaxis caused a rapid increase in circulating platelet-activating factor (PAF) levels. In turn, the elevated PAF contributes to the early phase of anaphylaxis as well as the subsequent activation of the nuclear factor (NF)-kappaB, a crucial transcription factor regulating the expression of many proinflammatory cytokines and immunoregulatory molecules. The induction of NF-kappaB activity is accompanied by TNF-alpha production, which, in turn, promotes late phase PAF synthesis. This secondary wave of PAF production leads eventually to the late phase of anaphylactic reactions. Mast cells do not appear to be required for development of the late phase anaphylaxis. Together, this work reveals the first mechanistic basis for biphasic anaphylactic reactions and provides possible therapeutic strategies for human anaphylaxis.

fig4: IL-1 is not an important mediator in developing a late phase anaphylactic reaction. (a) Comparison of mRNA expression between TNF-α and IL-1β during anaphylaxis. As a positive control, RNA was prepared at different time points from the lungs of 50-μg LPS-injected mice. (b) The late phase increase in plasma PAF and hematocrit value in IL-1R−/− mice. Blood was collected 7.5 h after challenge injection. Results for all panels are expressed as the mean ± SEM of three separate experiments (n = 3 for each time point).

Mentions:
Although IL-1 was not detected in the circulation during anaphylaxis by ELISA system, it is thought that even femtograms per milliliter of IL-1 can have pathophysiological activities (23, 24). Thus, to further clarify the role for IL-1 during anaphylaxis, we determined TNF-α and IL-1β mRNA levels in the lungs. A much weaker IL-1β mRNA expression was seen compared with the strong expression of TNF-α mRNA during anaphylaxis (Fig. 4 a). In contrast, LPS-induced IL-1β mRNA expression was comparable to that of TNF-α mRNA. Furthermore, similar levels of plasma PAF and hematocrit in the late phase were seen in IL-1R−/− mice (Fig. 4 b). These data indicate that IL-1 does not seem to play a significant role in Pen V–induced anaphylaxis.

fig4: IL-1 is not an important mediator in developing a late phase anaphylactic reaction. (a) Comparison of mRNA expression between TNF-α and IL-1β during anaphylaxis. As a positive control, RNA was prepared at different time points from the lungs of 50-μg LPS-injected mice. (b) The late phase increase in plasma PAF and hematocrit value in IL-1R−/− mice. Blood was collected 7.5 h after challenge injection. Results for all panels are expressed as the mean ± SEM of three separate experiments (n = 3 for each time point).

Mentions:
Although IL-1 was not detected in the circulation during anaphylaxis by ELISA system, it is thought that even femtograms per milliliter of IL-1 can have pathophysiological activities (23, 24). Thus, to further clarify the role for IL-1 during anaphylaxis, we determined TNF-α and IL-1β mRNA levels in the lungs. A much weaker IL-1β mRNA expression was seen compared with the strong expression of TNF-α mRNA during anaphylaxis (Fig. 4 a). In contrast, LPS-induced IL-1β mRNA expression was comparable to that of TNF-α mRNA. Furthermore, similar levels of plasma PAF and hematocrit in the late phase were seen in IL-1R−/− mice (Fig. 4 b). These data indicate that IL-1 does not seem to play a significant role in Pen V–induced anaphylaxis.

Bottom Line:
Using a murine model of penicillin V-induced systemic anaphylaxis, we show an autoregulatory cascade of biphasic anaphylactic reactions.The induction of NF-kappaB activity is accompanied by TNF-alpha production, which, in turn, promotes late phase PAF synthesis.This secondary wave of PAF production leads eventually to the late phase of anaphylactic reactions.

Affiliation:
Department of Immunology, University National Medical School, Chonju, Chonbuk, 561-182, South Korea.

ABSTRACTAnaphylaxis is a life-threatening systemic allergic reaction with the potential for a recurrent or biphasic pattern. Despite an incidence of biphasic reaction between 5 and 20%, the molecular mechanism for the reaction is unknown. Using a murine model of penicillin V-induced systemic anaphylaxis, we show an autoregulatory cascade of biphasic anaphylactic reactions. Induction of anaphylaxis caused a rapid increase in circulating platelet-activating factor (PAF) levels. In turn, the elevated PAF contributes to the early phase of anaphylaxis as well as the subsequent activation of the nuclear factor (NF)-kappaB, a crucial transcription factor regulating the expression of many proinflammatory cytokines and immunoregulatory molecules. The induction of NF-kappaB activity is accompanied by TNF-alpha production, which, in turn, promotes late phase PAF synthesis. This secondary wave of PAF production leads eventually to the late phase of anaphylactic reactions. Mast cells do not appear to be required for development of the late phase anaphylaxis. Together, this work reveals the first mechanistic basis for biphasic anaphylactic reactions and provides possible therapeutic strategies for human anaphylaxis.